title: Role of the haem oxygenase/carbon monoxide pathway in Clostridium difficile toxin A-induced enteritis in mice.
abstract: Clostridium difficile is the major cause of antibiotic-associated colitis, a disease with significant morbidity and mortality. This study investigated the role of the haem oxygenase-1 (HO-1)/carbon monoxide (CO) pathway in C. difficile toxin A-induced enteritis in mice. The HO substrate haemin, zinc protoporphyrin IX (ZnPP IX), a specific HO-1 inhibitor, dimanganese decacarbonyl (DMDC), a CO donor, or an equivalent volume of their respective vehicles were injected subcutaneously 30 min prior to local challenge with toxin A (25 or 50 µg per ileal loop) or PBS. Intestinal ileal loop weight/length ratios were calculated 3 h later. Ileal tissues were collected for histological analysis and measurement of myeloperoxidase (MPO) activity, tumour necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) production by ELISA and immunohistochemistry for HO-1. Treatment of mice subjected to C. difficile toxin A (TcdA) with haemin or DMDC prevented oedema, mucosal disruption and neutrophil infiltration observed in histological analysis. It also decreased TcdA-induced MPO activity and TNF-α or IL-1β production. In contrast, the specific HO-1 inhibitor (ZnPP IX) exacerbated all these evaluated parameters. TcdA increased HO-1 expression as seen by immunohistochemistry. These results suggest that the HO-1/CO pathway exerts a protective role in TcdA-induced enteritis and that its pharmacological modulation might be important for the management of C. difficile-associated disease.
authors.affiliation: Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil.|Department of Biomedical Sciences, State University of Rio Grande do Norte, Mossoró, Brazil.
authors.forename: C A
authors.initials: CA
authors.lastname: Medeiros
authors.affiliation: Division of Infectious Disease and International Health, Center for Global Health, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Warren
authors.affiliation: Division of Infectious Disease and International Health, Center for Global Health, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: R
authors.initials: R
authors.lastname: Freire
authors.affiliation: Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil.
authors.forename: C A
authors.initials: CA
authors.lastname: Vieira
authors.affiliation: Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil.
authors.forename: B B
authors.initials: BB
authors.lastname: Lima
authors.affiliation: Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil.
authors.forename: M L
authors.initials: ML
authors.lastname: Vale
authors.affiliation: Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil.
authors.forename: R A
authors.initials: RA
authors.lastname: Ribeiro
authors.affiliation: Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil.
authors.forename: M H
authors.initials: MH
authors.lastname: Souza
authors.affiliation: Department of Morphology, Federal University of Ceará, Fortaleza, Brazil.|Department of Physiology and Pharmacology, Federal University of Ceará, Fortaleza, Brazil.
authors.forename: G A
authors.initials: GA
authors.lastname: Brito
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D002248:Carbon Monoxide / Q000378:metabolism*; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000494:pharmacology; D004751:Enteritis / Q000139:chemically induced* / Q000517:prevention & control; D004768:Enterotoxins / Q000633:toxicity*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011524:Protoporphyrins / Q000494:pharmacology
chemical_list: D001427:Bacterial Toxins; D004768:Enterotoxins; D011524:Protoporphyrins; C416375:Ro 09-3431; C041348:tcdA protein, Clostridium difficile; C017803:zinc protoporphyrin; D006427:Hemin; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D003857:Deoxyuridine